A modified blood adult stem-cell transplant regimen has effectively reversed sickle cell disease in 9 of 10 adults who had been severely affected by the disease, according to results of a National Institutes of Health study in the Dec. 10 issue of the New England Journal of Medicine. The trial was conducted at the NIH Clinical Center in Bethesda, Md., by NIH researchers at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases.

"This trial represents a major milestone in developing a therapy aimed at curing sickle cell disease," said NIDDK Director Griffin P. Rodgers M.D., a co-author of the paper. "Our modified transplant regimen changes the equation for treating adult patients with severe disease in a safer, more effective way."

Sickle cell disease is caused by an altered gene that produces abnormal hemoglobin, the protein in normal red blood cells that carries oxygen throughout the body. When affected red cells lose oxygen, they collapse into a sickle, or C, shape and become stiff and sticky. Clumps of these cells block blood flow and can cause severe pain, organ damage from lack of oxygen, and stroke. Anemia often develops in people with the disease because sickle cells die off quickly and bone marrow does not make new ones fast enough.

In trials by other investigators, nearly 200 children with severe sickle cell disease were cured with bone marrow transplants after undergoing a regimen in which their own marrow was completely destroyed with chemotherapy. That regimen, however, had proven too toxic for adults, who have years of accumulated organ damage from the disease and are less able to tolerate complete marrow transplantation.

In contrast to the established method in children, this adult trial sought to reduce toxicity by only partially replacing the bone marrow. The much longer lifespan of normal red blood cells, compared to sickle red blood cells, allows the healthy cells to outlast and completely replace the disease-causing cells.

To achieve this goal, the investigators used a low dose of radiation to the whole body and two drugs, alemtuzumab and sirolimus, to suppress the immune system. Alemtuzumab depletes immune cells, but does not adversely affect blood stem cells. Sirolimus does not block the activation of immune cells, but inhibits their proliferation, creating a balance that potentially helps prevent rejection of the new stem cells.

The radiation favorably conditions the bone marrow, where donor stem cells move in and begin producing new, healthy red blood cells. After a median two and one half years follow-up, all 10 recipients were alive and sickle cell disease was eliminated in nine.

"Our patients have had a remarkable change in their lives," said John F. Tisdale, M.D., the trial's principal investigator in the NIH Molecular and Clinical Hematology Branch. "They are no longer being admitted to the hospital for frequent pain crises, they have been able to stop chronic pain medications, go back to school and work, get married and have children. Given these results, our regimen will likely have broad application to other nonmalignant diseases and can be performed at most transplant centers."

Transplanted cells or tissue are known as grafts. To reduce the possibility of the immune system's rejection of the graft or development of graft-versus-host disease, in which immune cells from the donor attack the recipient's tissues, investigators tested the patient and the potential donor to determine if they are a good immunological match. This is called human leukocyte antigen (HLA) typing.

The investigators performed HLA typing on 112 people with severe sickle cell disease and 169 healthy siblings. Of these, 10 patient-sibling identical matches were found. Blood stem cells collected from the blood of healthy donors were then infused into their siblings, ages 16 to 45 years.

This relatively low toxicity regimen allowed patients to become tolerant to the donor immune cells and to achieve stable mixed donor chimerism. Chimerism is a condition in which an individual has two genetically distinct types of cells in the blood. This mixture of host and donor cells was sufficient to reverse sickle cell disease. In most patients the donor's red blood cells completely replaced the recipient's.

"Remarkably, the treatment did not result in graft-versus-host disease for any of the participants," noted Susan B. Shurin, M.D., acting director of the NHLBI. GVHD is a common complication of stem cell transplantation and can lead to serious problems, such as rash, diarrhea and nausea, liver disease, or death. "We are continuing to explore better treatments with fewer side effects to help the millions of sickle cell patients worldwide. This is a very important study because it lessens the toxicity of a therapy known to be highly effective."

In the United States, approximately 80,000 people have sickle cell disease, found mainly in people of African ancestry. It occurs to a lesser extent in people of Hispanic, Middle Eastern, Asian and white ancestry. Worldwide, millions of people have sickle cell disease. The pain and complications associated with sickle cell disease can have a profound impact on patients' quality of life, ability to work, and long-term health and well-being.

One of the main obstacles in treating a larger number of African-Americans with sickle cell disease is the relative lack of an available HLA-matched donor. Dr. Tisdale explained, "Most white Americans can easily find a matched donor in the unrelated bone marrow or cord blood registries; yet when we screened a number of the people in our trial who were without an HLA-matched sibling donor, we could not find a compatible unrelated donor."

However, there may be a way beyond this health care disparity, Tisdale indicated. If participants in the current trial continue to do well with their transplants it may be possible to move to what he calls "haplo-transplantation," or a half-match from a sibling, parent or child. "This would allow most people with sickle cell disease to be treated and enjoy a better quality of life," he said.

The NIH Clinical Center's Department of Laboratory Medicine and Transfusion Medicine provided clinical laboratory and transfusion medicine support and patient care for the stem cell donors and transplantation recipients in trial. The Sidney Kimmel Cancer Center at Johns Hopkins Medical Institute provided conceptual input into the design of the trial's immunological component. The trial is registered as NCT00061568 in www.clinicaltrials.gov.

Health care providers — and sickle cell patients and family members who may be interested in joining NIH blood stem-cell transplant studies — may call 301-402-6466 for more information. Calls will be returned within 48 hours. To search for other clinical trials, visit www.clinicaltrials.gov.

The National Institute of Allergy and Infectious Diseases (NIAID) conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The NIH Clinical Center (CC) is the clinical research hospital for the National Institutes of Health. Through clinical research, physician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health. For more information, visit http://clinicalcenter.nih.gov.

Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at: www.nhlbi.nih.gov.

NIDDK, part of NIH, conducts and supports basic and clinical research and research training on some of the most common, severe and disabling conditions affecting Americans. The Institute's research interests include: diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic and hematologic diseases. For more information, visit www.niddk.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.